IκB kinase 2 but not NF-κB-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction
Although dendritic cells (DCs) are the most potent antigen-presenting cells involved in numerous physiologic and pathologic processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function. Recently, we demonstrated that nuclear factor (NF)-κB activ...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2003
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| _version_ | 1797100751414099968 |
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| author | Andreakos, E Smith, C Monaco, C Brennan, F Foxwell, B Feldmann, M |
| author_facet | Andreakos, E Smith, C Monaco, C Brennan, F Foxwell, B Feldmann, M |
| author_sort | Andreakos, E |
| collection | OXFORD |
| description | Although dendritic cells (DCs) are the most potent antigen-presenting cells involved in numerous physiologic and pathologic processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function. Recently, we demonstrated that nuclear factor (NF)-κB activation is central to that process, as overexpression of IκBα blocks the allogeneic mixed lymphocyte reaction (MLR), an in vitro model of T-cell activation. In this study, we investigated the role of 2 putative NF-κB-inducing components, NF-κB-inducing kinase (NIK), and IκB kinase 2 (IKK2). Using an adenoviral gene transfer method to efficiently express dominant-negative (dn) forms of these molecules in monocyte-derived DCs, we found that IKK2dn but not NIKdn inhibited the allogeneic MLR. When DCs were fixed, this inhibitory effect of IKK2dn was lost, suggesting that IKK2 is involved in T-cell-derived signals that enhance DC antigen presentation during the allogeneic MLR period and does not have an effect on viability or differentiation state of DCs prior to coculture with T cells. One such signal is likely to be CD40 ligand (CD40L), as IKK2dn blocked CD40L but not lipopolysaccharide (LPS)-induced NF-κB activation, cytokine production, and up-regulation of costimulatory molecules and HLA-DR in DCs. In summary, our results demonstrate that IKK2 is essential for DC activation induced by CD40L or contact with allogeneic T cells, but not by LPS, whereas NIK is not required for any of these signals. In addition, our results support IKK2 as a potential therapeutic target for the downregulation of unwanted immune responses that may occur during transplantation or autoimmunity. © 2003 by The American Society of Hematology. |
| first_indexed | 2024-03-07T05:42:03Z |
| format | Journal article |
| id | oxford-uuid:e5e839fc-d7c0-46ed-a79a-aad8456c5825 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:42:03Z |
| publishDate | 2003 |
| record_format | dspace |
| spelling | oxford-uuid:e5e839fc-d7c0-46ed-a79a-aad8456c58252022-03-27T10:27:25ZIκB kinase 2 but not NF-κB-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reactionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e5e839fc-d7c0-46ed-a79a-aad8456c5825EnglishSymplectic Elements at Oxford2003Andreakos, ESmith, CMonaco, CBrennan, FFoxwell, BFeldmann, MAlthough dendritic cells (DCs) are the most potent antigen-presenting cells involved in numerous physiologic and pathologic processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function. Recently, we demonstrated that nuclear factor (NF)-κB activation is central to that process, as overexpression of IκBα blocks the allogeneic mixed lymphocyte reaction (MLR), an in vitro model of T-cell activation. In this study, we investigated the role of 2 putative NF-κB-inducing components, NF-κB-inducing kinase (NIK), and IκB kinase 2 (IKK2). Using an adenoviral gene transfer method to efficiently express dominant-negative (dn) forms of these molecules in monocyte-derived DCs, we found that IKK2dn but not NIKdn inhibited the allogeneic MLR. When DCs were fixed, this inhibitory effect of IKK2dn was lost, suggesting that IKK2 is involved in T-cell-derived signals that enhance DC antigen presentation during the allogeneic MLR period and does not have an effect on viability or differentiation state of DCs prior to coculture with T cells. One such signal is likely to be CD40 ligand (CD40L), as IKK2dn blocked CD40L but not lipopolysaccharide (LPS)-induced NF-κB activation, cytokine production, and up-regulation of costimulatory molecules and HLA-DR in DCs. In summary, our results demonstrate that IKK2 is essential for DC activation induced by CD40L or contact with allogeneic T cells, but not by LPS, whereas NIK is not required for any of these signals. In addition, our results support IKK2 as a potential therapeutic target for the downregulation of unwanted immune responses that may occur during transplantation or autoimmunity. © 2003 by The American Society of Hematology. |
| spellingShingle | Andreakos, E Smith, C Monaco, C Brennan, F Foxwell, B Feldmann, M IκB kinase 2 but not NF-κB-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction |
| title | IκB kinase 2 but not NF-κB-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction |
| title_full | IκB kinase 2 but not NF-κB-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction |
| title_fullStr | IκB kinase 2 but not NF-κB-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction |
| title_full_unstemmed | IκB kinase 2 but not NF-κB-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction |
| title_short | IκB kinase 2 but not NF-κB-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction |
| title_sort | iκb kinase 2 but not nf κb inducing kinase is essential for effective dc antigen presentation in the allogeneic mixed lymphocyte reaction |
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